The increase of the elderly population in the urban areas of Argentina is comparable to that of many North American and European cities. Consequently, the incidence of age-related neurological pathologies is becoming a problem of significant medical and economic impact for the country. Unfortunately, research and development of novel therapeutic tools for neurodegenerative diseases, like gene therapy, remain virtually undeveloped in the country. In this context, the overall goal of the present proposal is to implement neurotrophic factor gene therapy in the brain of aging rats, using the genes for glial cell line-derived neurotrophic factor (GDNF) and insulin-like growth factor I (IGF-I), two neuroprotective molecules of growing clinical interest. Using the aging rat as an animal model of age- related decline in motor and cognitive function, we wish, on the one hand, to continue our collaborative studies with Dr. Martha Bohn on the ability of GDNF and IGF-I to rescue dysfunctional central Dopaminergic (DA) neurons, building on the results generated during an R21 grant awarded by the NIA and FIC to the PI. Secondly, we wish to further develop the exploratory studies started in 2006 in collaboration with Dr. William Sonntag, on the restorative ability of IGF-I gene delivery on cognitive function in aging rats. Specifically, we propose: 1) to implement long-term GDNF gene therapy in the hypothalamus (HPTL) of old (24 mo.) female rats, a well-established model of age-related DA neuron dysfunction;2) To determine whether combined GDNF and IGF-I gene therapy in the HPTL of senile rats results in a more effective neuroprotection than single trophic factor gene delivery. 3) To assess the neuroprotective activity of IGF-I gene therapy on the nigral DA neurons of senile (30 mo.) female rats. The treatment is intended to reverse the marked loss of nigral DA neurons in this animal model of Parkinson's disease (PD). 4) To implement peripheral (intramuscular) IGF-I gene therapy aimed at increasing serum IGF-I levels in aging rats which is expected to lead to an amelioration of their reduced hippocampal-dependent cognitive functions. Adeno associated and adenoviral vectors will be used for gene delivery to the appropriate target areas. The effects of the treatments on DA neuron populations will be assessed morphometrically. Hypothalamic and nigral DA function will be determined by measuring serum prolactin and performing motor tests, respectively. Profiting from the availability of very old rats (a unique model of spontaneous DA neuron loss) at the foreign site, the proposed work will focus on a relevant age-related neurodegenerative pathology (PD) as well as on age-related cognitive decline, thus addressing two areas of interest for the NIA. The project is also multidisciplinary (a feature encouraged by this PAR), encompassing the fields of neuroendocrinology, cognitive neuroscience and biotechnology. PUBLIC HEALTH RELEVANCE: The increase in life expectancy achieved by modern medicine has led to a progressive rise in the incidence of age-related neurodegenerative diseases like Alzheimer's and Parkinson's, with their destructive consequences on cognition and other brain functions. In this context, new biotechnological strategies like gene therapy and potent neuroprotective molecules like glial cell line-derived neurotrophic factor and insulin-like growth factor I, emerge as promising therapeutic tools for the prevention and treatment of these devastating pathologies.